Neuroplasticity and Parkinson's Disease

This PET scan reflects the decreased

dopamine activity of a Parkinson's

patient's brain (before and after)

compared to a normal person's brain.

Think of a hobby you enjoy doing and the satisfaction you get from it. That pleasant feeling you experience is directly correlated to dopamine levels and the substantia nigra in the brain. As you can imagine, diseases that cause a disruption in dopamine levels and affect synaptic plasticity in the substantia nigra would greatly affect an individual negatively, as seen in various neurological diseases. How can we further study these mechanisms and pathways to understand them better and potentially create new treatments?

A synaptic view of dopamine levels in a
              normal and a Parkinson's affected neuron.

  Dr. Kim Blackwell, from the Computational and Experimental Neuroplasticity Laboratory of the Krasnow Institute at George Mason University, held a lecture in my NEUR410 class regarding her research on the mechanisms involved in synaptic plasticity and it’s relation to diseases such as Parkinson’s and schizophrenia. The talk focused on dopamine, a neurotransmitter that affects brain processes that control movement, emotional responses, and the ability to experience pleasure and pain. A major brain structure that is involved with neuron containing dopamine is the substantia nigra. As Blackwell mentioned, the substantia nigra is located in the mid brain and is an important component involved with rewards, addiction, and movement. Decreased dopamine levels in the substantia nigra will affect that brain structure, inhibiting neuronal plasticity and as a result cause diminished motor function, emotional instability, and learning impairment; some of which are seen in Parkinson’s disease..

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According to Dr. Blackwell’s experiments, theta burst stimulation in post mortem brain slices showed strong positive correlation between synaptic plasticity and long term potentiation (LTP) and long term depression (LDP). In order to further differentiate these two pathways, Dr. Blackwell and her team observed the spatial and temporal signaling pathways. To determine if dopamine and calcium activated signaling pathways discriminate temporal patterns, they measured the following responses of molecules CKCam, PKA, pS831, and pS845 to theta molecules different from the brain’s normal 20 Hz. While only CKCam showed discrimination at the time, Dr. Blackwell later learned that it was not the only one because dopamine interaction with Acetylcholine activated Gq couple pathways and so were molecules 2AG (LTP), PKC (Chemical LTP), and endocanabonoid. She determined that the brain actually releases receptors that bind to those molecules. Dr. Blackwell specified temporal specificity even further and concluded that theta bursts enhances PKC more than 2AG which results in LTP because the PKC effect dominates. This suggests that PKC is essential for LTP so to confirm it, an experimental test was conducted. Chelerythrine, a PKC inhibitor, showed non-specific time dependent effects thus confirming PKC is needed for LTP. Learning, memory, and movement will be affected as these different molecules influence the plasticity of LTP and LTD synaptic models.

A deep brain stimulation (DBS) device for
               treatment of symptoms of Parkinson's disease.

In the future, Dr. Blackwell and her team plan to continue experiments ensuring characteristics of plasticity. Those studies will include dopamine dependent plasticity and models of how network activity changes during habit learning, dopamine depletion, and drug abuse. She did a very good job describing the work she is doing and had a funny sense of humor which kept the audience interested. Although there was a lot of information being presented, I did not fully understand it all immediately but the notes from her slides that I copied down were clear and straightforward which eased the understanding process later. Her research is definitely moving neuroscience to further understand the importance of specific molecules and their roles in mechanisms involving LDP, LTP, learning, memory, and movement. Although Dr. Blackwell's work covers more research, this lecture was heavily geared towards Parkinson's. Currently, there is medication therapy to replenish the lost dopamine and deep brain stimulation devices to treat symptoms of Parkinson's  but none are very effective long term and have numerous side effects. Dr. Blackwell's work may open new doors to how to we treat this disease. Perhaps through her research, a more effective drug will be discovered that treats the disease as well as prevents the brain from building tolerance at such a high rate, like many medications do today. Her research will also allow us to understand drug abuse better at the molecular level and the effects of dopamine at different regions of the brain, not to mention how the brain learns and expands plasticity.

Image references

http://medgadget.com/2009/01/european_unions_approves_deep_brain_stimulation_s ystems_for_parkinsons.html

http://www.bio12.com/ch17/IBNervous/Parkinson'sDopamine.jpg

http://biomed.brown.edu/Courses/BI108/BI108_2008_Groups/group07/PET_scan_Parkinson's_Disease.jpg

http://www.pennmedicine.org/encyclopedia/ency_images/encymulti/images/en/19515.jpg